Human immunodeficiency virus (HIV) infection of host cells initiates innate immune signaling pathways that result in the expression of type I interferons and proinflammatory cytokines that interfere with the life cycle of the virus. The virus can bring about measures that not only allow it to escape detection within the cell, but also to use the components of the immune signaling pathways for its own advantage. Studies of mechanisms by which HIV evades the antiviral innate immune responses provide the scientific impetus to characterize the genetic polymorphisms that can affect components of the host signaling pathways. We will conduct a cohort study to determine whether the host proteins identified by genomewide functional screens for which a plausible biological mechanism of action for the gene is found contributes to HIV/AIDS susceptibility. We will look at the association between genetic variants (both known and previously unknown) and HIV/AIDS susceptibility using biological samples and information obtained from men enrolled in the Multicenter AIDS Cohort Study (MACS). This will allow us to undertake detailed studies of sufficient sample size to distinguish the proposed effect of a factor of functional relevance from no effect convincingly. Our objective is to undertake a holistic approach to the systematic examination of how the virus and antiviral innate immune responses intersect to discover how the patterns of genetic variation and differences in gene expression of the factors that are involved in signaling pathways may contribute to HIV disease. The rationale for our approach is that each of the described hostrelated factors are relevant to only a small proportion of people who continue to resist HIV/AIDS. Defining how HIV subverts the innate immune response is thus important for systemslevel understanding of the innate immune response and rational design of improved therapies. Our specific aims are to: distinguish polymorphisms most likely to affect function ofthe systematically identified network of genes underlying the innate immune response to HIV infection; and examine the association between genetic polymorphism in the candidate innate immune response genes and HIV/AIDS susceptibility. Through collaboration with the other Projects, we will collect a comprehensive quantitative data set to attain systemslevel understanding of antiviral innate immune responses.